Scientists Unveil Structure of Molecular Target of Many Drugs

BETHESDA, MD.,Oct. 29, 2007--More than 40 years after beta
blockers were first used clinically, scientists can finally get a
close-up look at the drugs' molecular target-the ?2-adrenergic
receptor. The work is particularly exciting because it offers the
first glimpse into an important, but scientifically elusive family
of human proteins called G protein-coupled receptors (GPCRs).

Because GPCRs control critical bodily functions, several of our
senses, and the action of about half of today's pharmaceuticals,
the research promises not only to speed the discovery of new and
improved drugs, but also to broaden our understanding of human
health and disease.

Published online in the October 25 issue of Science Express, the
research was supported by two major initiatives of the National
Institutes of Health-the Roadmap and the Protein Structure
Initiative (PSI), which is led by the National Institute of General
Medical Sciences. Additional funding came from the National
Institute of Neurological Disorders and Stroke.

The work represents a technical tour de force that required the
scientists to devise several new techniques. Many of the
difficulties arose because the receptor is a membrane protein-one
of the trickiest molecules to capture in three-dimensional detail.
The only other known GPCR structure comes from a cow and was
determined in 2000.

"Because of their role in so many medically important processes
and the great challenges they present for detailed study, membrane
proteins have been one focus of the NIH Roadmap for Medical
Research," said NIH Director Elias A. Zerhouni, M.D. "The
determination of this structure is an exciting example of the
rewards of the Roadmap investment."

After considerable efforts with the protein in a natural form,
the researchers, led by Raymond Stevens of The Scripps Research
Institute and Brian Kobilka of Stanford University, turned to
protein engineering. To overcome problems with the protein's
floppiness, they replaced part of the protein with another, stiffer
molecule, essentially clamping the protein into place so they could
work with it more easily. They also utilized several new methods to
minimize the amount of the protein needed for detailed structural
studies.

"This is an absolutely remarkable advance," said Jeremy M. Berg,
Ph.D., director of NIGMS which, in addition to spearheading the
PSI, plays a leading role in the membrane protein Roadmap
initiative. "Many laboratories around the world are trying to
reveal the secrets of these proteins and this new structure takes
this field to a new level."

NIGMS (<http://www.nigms.nih.gov>)
supports basic biomedical research that is the foundation for
advances in disease diagnosis, treatment, and prevention.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human
Services. It is the primary federal agency for conducting and
supporting basic, clinical and translational medical research, and
it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs,
visit www.nih.gov.

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